POS0030 METHOTREXATE USE ASSOCIATES WITH ISCHEMIC CARDIOVASCULAR RISK REDUCTION IN MALES BUT NOT FEMALES WITH RHEUMATOID ARTHRITIS
Authors: G. Karpouzas, S. Ormseth, P. Van Riel, C. S. Crowson, E. Myasoedova, S. Gabriel, M. A. González-Gay, A. Corrales, S. Rantapää Dahlqvist, P. Sfikakis, P. Dessein, L. Tsang, C. Hitchon, H. El-Gabalawy, V. Pascual, I. J. Colunga-Pedraza, D. Á. Galarza-Delgado, J. R. Azpiri-López, S. Rollefstad, A. G. Semb, D. P. Misra, G. Kitas, E. M. Hauge
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) experience higher cardiovascular risk compared to individuals without inflammatory rheumatic disease. Observational studies indicate that methotrexate (MTX) may decrease cardiovascular risk in patients with RA. It is, however, unclear whether sex differentially impacts cardiovascular risk in MTX users and non-users and whether men and women derive equal benefit from methotrexate use. <h3>Objectives</h3> We here explored the influence of sex on cardiovascular risk in MTX nonusers and users. We further evaluated the effect of MTX treatment on cardiovascular risk in males and females with RA. <h3>Methods</h3> We evaluated 4362 patients with RA and no atherosclerotic cardiovascular disease, prospectively included in an international observational cohort [<i>A</i>n In<i>t</i>ernation<i>a</i>l <i>C</i>ardiovascular <i>C</i>onsortium for people with <i>RA</i> (ATACC-RA)]. Outcomes of interest were (a) major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction or stroke and (b) any ischemic cardiovascular events (CVE) including MACE, stable angina, coronary revascularization, transient ischemic attack and peripheral arterial disease with or without revascularization. Missing covariate data were imputed using multiple imputation with 10 repetitions. Multivariable Cox models stratified by center evaluated the impact of sex, baseline MTX use and their interaction on CVE risk after adjusting for age, hypertension, diabetes, family history of coronary artery disease, smoking, total cholesterol to high-density lipoprotein cholesterol ratio, disease duration, and disease activity score (DAS28 ESR). Two corroborating sensitivity analyses were conducted; The first used inverse probability of treatment weights to balance differences in MTX treated and untreated patients. The second included patients enrolled in the cohort on or after January 1, 2000, when MTX use became more prevalent among enrollees. <h3>Results</h3> There were 237 first MACE and 358 total ischemic CVE recorded during the entire follow-up period. Male sex associated with an 81% and 58% greater risk of MACE and any ischemic CVE, respectively (Figure 1). Among MTX nonusers, incidence of MACE and any ischemic CVE was higher in males [17.6 (95% CI 14.4-21.3) and 24.5 (20.7-28.9) events/1000PY, respectively] compared to females [6.9 (5.7-8.4) and 11.4 (9.8-13.3) events/1000PY respectively, all p for difference&lt;0.001]. In adjusted Cox models, male nonusers had a 2.09-fold higher risk of MACE and 74% higher risk of any ischemic CVE compared to female nonusers (both p&lt;0.001, Figure 1). In contrast, among MTX users, incidence of MACE and any ischemic CVE was not significantly different in males [4.2 (1.7-10.0) and 7.6 (4.0-14.6) events/1000PY, respectively] than females [6.4 (4.4-9.2) and 9.4 (6.9-12.8) events/1000PY, respectively] and sex was not associated with event risk in MTX users in adjusted models. Moreover, among males, MTX use associated with a 66% reduced risk of MACE and 55% reduction in any ischemic CVE (p=0.026 and 0.024, respectively). In contrast, MTX use was not associated with MACE or any ischemic CVE in females [adjusted hazard ratio 1.33 (0.83-2.14) and 1.21 (0.81-1.79) respectively]. Both sensitivity analyses yielded similar results. <h3>Conclusion</h3> RA males not using MTX exhibit higher risk of MACE and any ischemic CVE compared to female nonusers, while no differences are observed between male and female MTX users. Baseline MTX use associated with reduction in the risk of MACE and all ischemic cardiovascular events in males but not females with RA. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> George Karpouzas Speakers bureau: Sanofi/Genzyme/Regeneron, BMS, Consultant of: Sanofi/Genzyme/Regeneron, Janssen, Grant/research support from: Pfizer, Sarah Ormseth: None declared, Piet van Riel: None declared, Cynthia S. Crowson: None declared, Elena Myasoedova: None declared, Sherine Gabriel: None declared, Miguel A González-Gay: None declared, Alfonso Corrales: None declared, Solbritt Rantapää Dahlqvist: None declared, Petros Sfikakis: None declared, Patrick Dessein: None declared, Linda Tsang: None declared, Carol Hitchon: None declared, Hani El-Gabalawy: None declared, Virginia Pascual: None declared, Iris Jazmin Colunga-Pedraza: None declared, Dionicio Ángel Galarza-Delgado: None declared, José Ramón Azpiri-López: None declared, Silvia Rollefstad: None declared, Anne Grete Semb: None declared, Durga Prasanna Misra: None declared, George Kitas: None declared, Ellen-Margrethe Hauge: None declared.